Profile of selumetinib and its potential in the treatment of melanoma

Kim, Dae Won; Patel, Sapna

doi:10.2147/ott.s51596

Cited by 16 publications

(12 citation statements)

References 56 publications

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“…This sensitivity was very close to the least sensitive of the melanoma lines, SKmel5, where its cell viability was reduced to just 51.80% at the same concentration (Table 1 ). Overall, these findings are in support of previous work showing that melanoma cells are more sensitive to MEK inhibition than normal cells, with drug sensitivity to selumetinib in the same range as detected here (as previously reviewed [ 35 ]).…”

Section: Resultssupporting

confidence: 93%

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

et al. 2017

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Cutaneous melanoma, which develops from the pigment producing cells called melanocytes, is the most deadly form of skin cancer. Unlike the majority of other cancers, the incidence rates of melanoma are still on the rise and the treatment options currently available are being hindered by resistance, limited response rates and adverse toxicity. We have previously shown that an FDA approved drug leflunomide, used for rheumatoid arthritis (RA), also holds potential therapeutic value in treating melanoma especially if used in combination with the mutant BRAF inhibitor, vemurafenib. We have further characterized the function of leflunomide and show that the drug reduces the number of viable cells in both wild-type and BRAFV600E mutant melanoma cell lines. Further experiments have revealed leflunomide reduces cell proliferation and causes cells to arrest in G1 of the cell cycle. Cell death assays show leflunomide causes apoptosis at treatment concentrations of 25 and 50 µM. To determine if leflunomide could be used combinatorialy with other anti-melanoma drugs, it was tested in combination with the MEK inhibitor, selumetinib. This combination showed a synergistic effect in the cell lines tested. This drug combination led to an enhanced decrease in tumor size when tested in vivo compared to either drug alone, demonstrating its potential as a novel combinatorial therapy for melanoma.

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Section: Resultssupporting

confidence: 93%

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

et al. 2017

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“…Although the MEK-inhibitor selumetinib did not improve survival in cutaneous melanoma, when administered to uveal melanoma patients with GNAQ mutation it extended progression-free survival. 168 , 169 The main limitation of MAPK inhibitors is that the drug is effective for an average of 6-10 months and it is believed this leads to more aggressive recurrences.…”

Section: Introductionmentioning

confidence: 99%

Uveal Melanoma; Current Trends in The Diagnosis and Management

Tarlan

Kıratlı

2016

tjo

104

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Uveal melanoma, which is the most common primary intraocular malignancy in adults, arises from melanocytes within the iris, ciliary body and choroid. The diagnosis is based principally on clinical examination of the tumor with biomicroscopy and indirect ophthalmoscopy and confirmed by diagnostic techniques such as ultrasonography, fundus fluorescein angiography and optical coherence tomography. The clinical diagnosis of posterior uveal melanomas can be made when the classical appearance of a pigmented dome-shaped mass is detected on dilated fundus exam. Uveal melanomas classically show low to medium reflectivity on A-scan ultrasonography and on B-scan ultrasonography the tumor appears as a hyperechoic, acoustically hollow intraocular mass. Management of a suspicious pigmented lesion is determined by its risk factors of transforming into a choroidal melanoma, such as documentation of growth, thickness greater than 2 mm, presence of subretinal fluid, symptoms and orange pigment, margin within 3 mm of the optic disc, and absence of halo and drusen. Advances in the diagnosis and local and systemic treatment of uveal melanoma have caused a shift from enucleation to eye-conserving treatment modalities including transpupillary thermotherapy and radiotherapy over the past few decades. Prognosis can be most accurately predicted by genetic profiling of fine needle aspiration biopsy of the tumor before the treatment, and high-risk patients can now be identified for clinical trials that may lead to target-based therapies for metastatic disease and adjuvant therapy which aims to prevent metastatic disease.

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“…KO samples treated with trametinib, compared to the control (Figure 2a,b and Figure S1c). We checked the resistance effect of these cell lines toward an additional potent and highly selective MEK1/2 inhibitor, selumetinib, (Kim & Patel, 2014) and received similar results (Figure 2c,d). These data confirm that KO of FBXO42…”

Section: A Function-based Genomic Screen In Nrasmutant Melanoma Celmentioning

confidence: 79%

A genome‐wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS‐mutant melanoma

Nagler

Vredevoogd

Alon

et al. 2019

Pigment Cell Melanoma Res

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NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway‐targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK‐targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole‐genome CRISPR‐Cas9 knockout screen identified the target Kelch domain‐containing F‐Box protein 42 (FBXO42) as a factor involved in NRAS‐mutant melanoma‐acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS‐mutant melanoma cells. Our findings thus show a new pathway involved in NRAS‐mutant melanoma resistance and provide new opportunities for novel therapeutic options.

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Profile of selumetinib and its potential in the treatment of melanoma

Cited by 16 publications

References 56 publications

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

The anti-rheumatic drug, leflunomide, synergizes with MEK inhibition to suppress melanoma growth

Uveal Melanoma; Current Trends in The Diagnosis and Management

A genome‐wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS‐mutant melanoma

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